The work described in this proposal represents a multidisciplinary, integrated approach to understanding the effects of normal aging in brain systems that support cognitive functions affected in humans as they age. It is focused on individual differences in cognitive decline and brain aging in hippocampal/cortical systems. Three Cores (Administrative, Animal Resource, and Bioinformatics/Data Management) serve all of the participating investigators conducting research in four projects. An important feature of the research program is the use of brain material from a common source, with neurobiological analyses conducted against the background of cognitive assessment using healthy male Long Evans rats. The broad spectrum of cognitive outcomes at older ages (24-28 mo) in this study population consists of impairment affecting 50-60% of the population, while the remaining aged cohorts fall within the range of young adults (4-6 mo). Significant progress in the current funding period has occurred in the understanding of neurocognitive aging as a functional disorder of aged rats with cognitive deficits, affecting specific encoding properties and plasticity mechanisms within the hippocampal system. Our findings demonstrate a particularly prominent effect of aging on the CAS region, an area less fully studied in aging research compared to CA1. Going forward, our work in the model will expand the scope of neural plasticity studies in other isolated pathways in the in vitro hippocampal slice. An additional highlight of our recent work is increasing support for the concept of differential adaptive aging, namely that the preservation of cognitive function is associated with adaptive neurobiological changes that distinguish those older animals from both young adults and aged rats with cognitive deficits. Our proposed plans will build on our achievements, exploiting recent findings to embark on new lines of investigation to modify aging outcomes. We will use interventions based on the data obtained in our model to test specific scientific hypotheses with implications for translation into new therapeutic approaches. In addition to, treatment effects on behavioral/cognitive outcomes, our approach will examine effects of interventions on key neurobiological markers of neurocognitive aging in the hippocampal system, to include properties of CAS neurons, which are hyperactive and fail to encode new representations, along with transcriptional markers (both basal expression and learning-activated) that are seen in the condition of age-related impairment. Finally, we will begin a program of research to examine whether signatures of neurocognitive aging in subregions of the hippocampal system in rats have a counterpart in aged monkey brains. That work will be important to indicate whether interventions based on the study of neurocognitive aging in the rodent brain would potentially be effective in non-human primates.